Project Summary The overall goal of this research is to better understand the analgesic properties of central noradrenergic systems. Emotional regulation in the face of physical injury and psychological trauma is critical to long-term survival and quality of life. Uncontrollable anxiety, anhedonia, and depression often result following periods of prolonged stress or chronic pain. Both chronic pain and stress lead to overlapping physiological adaptations such that the same tricyclic and serotonin/norepinephrine reuptake inhibitors (SNRIs) developed and used to treat depression are also effective in treating chronic pain. Therefore, norepinephrine (NE) is likely one of the key neurotransmitters regulating pain processing during stress. In this proposal we seek to define the role of NE in stress-induced modification of pain. The locus coeruleus-noradrenergic (LC-NE) system is one particular central nervous system target that holds promise for interventions in both chronic pain and stress-induced psychiatric disorders. This research focuses on understanding the mechanisms by which the LC-NE system modulates endogenous analgesia and how chronic stress affects this system. The central hypothesis of this proposal is that LC-NE neuronal activity is critical for stress-induced modulation of nociception. The first aim of this proposal will assess the role of LC-NE neurons in acute stress-induced antinociception using in vivo optogenetics and chemogenetics. The second aim seeks to understand the mechanism for the transition from acute stress-induced antinociception to chronic stress-induced pronociception. In particular, this aim seeks to determine whether repeated LC-NE stimulation from repeated stress exposure drives stress-induced pronociception. To do so we will use, using in vivo optogenetics, chemogenetics, and intersectional genetic models to remove LC-NE function during repeated restraint stress. The final aim seeks to clarify how two different models for studying chronic stress reveal opposing pain-related phenotypes. Here, we will use brain slice electrophysiology and in vivo fiber photometry to monitor LC-NE activity following these stress paradigms and in response to noxious stimuli. Together these experiments will generate previously unattainable information about LC-NE neurons and associated efferent circuitry that regulate the pain-related behaviors in response to stressors. These studies will define the role of the LC-NE system; 1) in acute stress-induced analgesia, 2) the transition to chronic stress-induced hyperalgesia, and 3) identify mechanisms by which different forms of stress alter LC-NE function and nociception. This information will be critical for translational research targeting the noradrenergic system in the treatment of pain and neuropsychiatric disorders.